PROJECT SUMMARY: Ovarian cancer remains the most deadly malignancy. Targeting angiogenesis is a particulariy attractive strategy because of the presumed genetic stability of endothelial cells. This is best illustrated by recent successes of anti-angiogenic therapy (e.g., bevacizumab) in patients with solid tumors. However, despite initial responses, most patients eventually develop tumor progression resulting in their demise. Therefore, new anti-angiogenesis therapeutic strategies are needed. The overall goal of this project is to develop novel nanoparticle-based strategies to target the tumor vasculature specifically. We propose to utilize two types of biocompatible therapeutic nanoparticles (chitosan and gold nanoshell nanoparticles) for the delivery of therapeutic payloads (e.g., siRNA) or near-infrared (NIR) laser mediated thermal ablation. These platforms are supported by Integrated approaches for selective delivery into the tumor vasculature using either rationally designed multi-stage carriers or surface ligands (thioaptamers) selected from screening libraries based on selective binding. Using genomic approaches, we have identified novel candidate target genes in ovarian cancer vasculature that will be targeted using RNAi approaches (Aim 1) because many are difficult to inhibit with small molecules or monoclonal antibodies. In our preliminary findings, we have identified thiophosphate oligonucleotide aptamers (thio-aptamers) that selectively bind to tumor, but not to normal endothelial cells based on counter selection strategies using freshly isolated endothelial cells from human ovarian cancer or normal ovaries. In Aim 1, we will develop thioaptamertargeted nanoparticles for selective delivery of therapeutic siRNA. On the basis of our preliminary findings regarding the critical role of size and shape in vascular localization of nanoparticles, we will pursue rational design of nanoparticles for targeting the tumor vasculature in Aim 2. Gold-based nanoshells offer unique opportunities for thermal ablation using NIR light. In Aim 3, we will develop and characterize novel approaches for thermal ablation of ovarian cancer vasculature using targeted gold nanoshells. All three aims are complementary to each other and findings of this study should allow the design and translation of new therapeutic approaches for women with ovarian cancer.